rs885838

Variant names:

• chr3-184378790-A-G
• rs885838
• NM_001290003.1:c.-28-413T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-184378790-A-G
• chr3-184378790-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001290003.1(THPO):​c.-28-413T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 984,546 control chromosomes in the GnomAD database, including 122,432 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (18937 hom., cov: 32)
  • Exomes 𝑓: 0.50 (103495 hom.)
• Consequence: THPO NM_001290003.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 12 publications found

Genes affected

THPO (HGNC:11795): (thrombopoietin) Megakaryocytopoiesis is the cellular development process that leads to platelet production. The main functional protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene. Mutations in this gene are the cause of thrombocythemia 1. Alternative promoter usage and differential splicing result in multiple transcript variants differing in the 5' UTR and/or coding region. Multiple AUG codons upstream of the main open reading frame (ORF) have been identified, and these upstream AUGs inhibit translation of the main ORF at different extent. [provided by RefSeq, Feb 2014]

THPO Gene-Disease associations (from GenCC):

• thrombocythemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• congenital amegakaryocytic thrombocytopenia

  Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• thrombocytopenia 9

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• familial thrombocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary isolated aplastic anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary thrombocytosis with transverse limb defect

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital amegakaryocytic thrombocytopenia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289500 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290003.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	NM_001290003.1		c.-28-413T>C		intron	N/A	NP_001276932.1	A0A3B3ITS0
	THPO	NM_001289998.1		c.-448-413T>C		intron	N/A	NP_001276927.1	P40225-1
	THPO	NM_001290028.1		c.-146+801T>C		intron	N/A	NP_001276957.1	P40225-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THPO	ENST00000645603.2		c.-28-413T>C		intron	N/A	ENSP00000494281.2	A0A3B3ITS0
	THPO	ENST00000649095.1		c.-28-413T>C		intron	N/A	ENSP00000497904.1	A0A3B3ITS0
	THPO	ENST00000876539.1		c.-145-2386T>C		intron	N/A	ENSP00000546598.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75118 AN: 151918 Hom.: 18916 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.541

GnomAD4 exome AF: 0.497 AC: 414169 AN: 832510 Hom.: 103495 Cov.: 29 AF XY: 0.497 AC XY: 190935 AN XY: 384464

African (AFR) AF: 0.526 AC: 8298 AN: 15770

American (AMR) AF: 0.635 AC: 624 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 2836 AN: 5150

East Asian (EAS) AF: 0.373 AC: 1354 AN: 3628

South Asian (SAS) AF: 0.460 AC: 7569 AN: 16448

European-Finnish (FIN) AF: 0.359 AC: 99 AN: 276

Middle Eastern (MID) AF: 0.565 AC: 914 AN: 1618

European-Non Finnish (NFE) AF: 0.497 AC: 378522 AN: 761356

Other (OTH) AF: 0.511 AC: 13953 AN: 27282

GnomAD4 genome AF: 0.495 AC: 75188 AN: 152036 Hom.: 18937 Cov.: 32 AF XY: 0.489 AC XY: 36330 AN XY: 74328

African (AFR) AF: 0.517 AC: 21435 AN: 41446

American (AMR) AF: 0.596 AC: 9114 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1919 AN: 5164

South Asian (SAS) AF: 0.455 AC: 2190 AN: 4812

European-Finnish (FIN) AF: 0.347 AC: 3670 AN: 10566

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33179 AN: 67976

Other (OTH) AF: 0.540 AC: 1140 AN: 2110

Alfa AF: 0.504 Hom.: 33271

Bravo AF: 0.515

Asia WGS AF: 0.453 AC: 1579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.38
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs885838; hg19: chr3-184096578;